Project Summary Myelodysplastic syndromes (MDS) are generally thought of as indolent conditions, but a significant number of patients have high-risk disease that carries a median survival less than 6 months. An allogeneic bone marrow transplantation (alloBMT) is the only curative option. Over the past two decades, we have pioneered strategies that dramatically improved the safety of alloBMT especially for the elderly, but despite these advances, approximately half of MDS patients will eventually relapse. Thus, disease relapse is now by far the major reason for failure of alloBMT. In several hematologic malignancies, additional post-alloBMT therapies can dramatically reduce the relapse rate; for example, BCR-ABL inhibitors can double the cure rate in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients. These strategies are especially effective when relapse is detected early, and in Ph+ ALL, BCR-ABL transcript provides a sensitive and specific measurement of minimal residual disease (MRD). In MDS, it is well recognized that there are no disease-defining genetic alterations and the mutational landscape of MDS can change with therapy or during progression to acute myeloid leukemia (AML). Therefore, we lack the ability to use genetically based strategies to uniformly detect MRD in MDS. The goal of the current proposal is to define the population of patients at high-risk for post-alloBMT relapse and depict the molecular signature of residual clones responsible for disease recurrence. Moreover, we plan to define the utility of plasma-based mutation detection as a minimally invasive MRD assay. We propose to study molecular MRD in serial MDS and AML plasma and/or serum samples available from 2 clinical trials (BMT CTN-0402 and 0201) . In aim 1, we will establish the sensitivity and specificity of plasma- derived circulating tumor DNA (ctDNA). We will study paired bone marrow and plasma samples from MDS and AML at the time of diagnosis and after alloBMT. In aim 2, we will determine the relationship between personalized post-alloBMT MRD detection and its impact on clinical outcomes. We will utilize 579 plasma/serum samples collected from 144 patients enrolled in 2 prospective alloBMT trials: BMT CTN-0201 and BMT CTN-0402. Through our aims, we will establish the utility of plasma-based personalized MRD testing as a predictive biomarker of relapse following alloBMT. Additionally, our studies will better define the molecular profile of resistant clones that may lead to development of personalized targeted maintenance therapies.